Abuse-resistant pharmaceutical composition for the treatment of opioid dependence

ABSTRACT

There is provided pharmaceutical compositions for the treatment of e.g. opioid dependency comprising microparticles of a pharmacologically-effective amount of buprenorphine, or a pharmaceutically-acceptable salt thereof, in associative admixture with particles comprising a weak acid, or particles comprising weakly-acidic buffer forming materials. The composition may further comprise a disintegrant and/or particles of a pharmacologically-effective amount of naloxone, or a pharmaceutically-acceptable salt thereof. The compositions are useful in the treatment of opioid dependency/addiction and/or pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/499,645, filed Apr. 27, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/261,571, filed Sep. 9, 2016, now abandoned,which is a continuation of U.S. patent application Ser. No. 14/577,823,filed Dec. 19, 2014, now issued as U.S. Pat. No. 9,439,900, which is acontinuation of U.S. patent application Ser. No. 14/127,470, now issuedas U.S. Pat. No. 8,940,330, which is a national stage application under35 U.S.C. § 371 of PCT Application No. PCT/GB2012/052303, filed 18 Sep.2012, which claims the priority benefit of U.S. Provisional ApplicationSer. No. 61/536,180 filed 19 Sep. 2011.

This invention relates to new pharmaceutical compositions comprisingopioids that are useful in the treatment of opioid/opiate dependencyand/or pain, which compositions may be abuse-resistant, and may beadministered transmucosally and, in particular, sublingually.

Opioids are widely used in medicine as analgesics. Indeed, it ispresently accepted that, in the palliation of more severe pain, no moreeffective therapeutic agents exist.

Opioid agonist analgesics are used to treat moderate to severe, chroniccancer pain, often in combination with non-steroidal anti-inflammatorydrugs (NSAIDs), as well as acute pain (e.g. during recovery from surgeryand breakthrough pain). Further, their use is increasing in themanagement of chronic, non-malignant pain.

A perennial problem with potent opioid agonists however is one of abuseby drug addicts. Drug addiction is a worldwide problem of which opioiddependence, notably of heroin, is a major component. The World HealthOrganisation (WHO) estimates that there are approximately 4.3 millionopioid addicts globally, with approximately 0.7 million in Europe and0.3 million in the US and Canada.

Opioid dependence is a major health problem and long-term heroin use isconnected to a substantially increased risk of premature death from drugoverdoses, violence and suicide. Furthermore, sharing of needles amongaddicts contribute to the spreading of potentially fatal bloodinfections such as HIV, and hepatitis C. In addition, opioid dependenceoften leads to difficulties with social relations, inability to manage anormal job and increased criminality to finance addiction, with severeimplications for the opioid dependent person and his/her family.

Opioid addicts not only feed their addition by direct purchase ofopioids “on the street”, typically in the form of opioid-based powders(such as heroin), but may also get hold of pharmaceutical formulationsintended for the treatment of e.g. pain. Such individuals then oftenapply innovative techniques in their abuse of such formulations, forexample by extracting a large quantity of active ingredient from thatformulation into solution, which is then injected intravenously. Withmost commercially-available pharmaceutical formulations, this can bedone relatively easily, which renders them unsafe or “abusable”. Thus,there is a general need for non-abusable pharmaceutical formulationscomprising opioid agonists.

Opioid addicts are often treated by way of “substitution” therapy, inwhich mainly “street” opioids of unknown strength and purity arereplaced by pharmaceutical-grade opioids with a longer duration ofaction, such as buprenorphine.

Further, a new cohort of opioid-dependent individuals has begun toemerge in the last decade, particularly in the US, namely so-called“white collar” addicts, who have become dependent upon prescriptionopioids, typically initiated for the treatment of pain. Substitutiontherapy is also required for this growing group of patients.

SUMMARY OF THE INVENTION

Opioid antagonists are used to reverse the pharmacological effects ofopioids. Selective opioid antagonists, such as naloxone, may thereforebe used to treat narcotic drug overdose or to diagnose suspected opioidaddiction. Naloxone in particular has a poor bioavailability whenadministered transmucosally but is rendered fully bioavailable whenadministered by injection.

A simple mixture combination tablet comprising the opioid partialagonist buprenorphine and naloxone in a 4:1 ratio for sublingualadministration is available under the trademark Suboxone®. (This andother abuse-resistant opioid-containing formulations are reviewed byFudula and Johnson in Drug and Alcohol Dependence, 83S, S40 (2006). Seealso US patent applications US 2003/0124061 and US 2003/0191147.)

Because of naloxone's poor transmucosal bioavailability, if Suboxone istaken sublingually, as directed, the small amount of naloxone that isabsorbed should not interfere with the desired effects of buprenorphine.

On the other hand, if Suboxone is dissolved and injected by an addictwith a view to achieving a “high”, the increased availability ofnaloxone via the parenteral route should serve to antagonize the effectsof buprenorphine, at the same time as precipitating unpleasant opioidwithdrawal symptoms in an individual physically dependent on opioids.

Nonetheless, when administered parenterally, naloxone's functionalblockade of buprenorphine's action is also only partial and isshort-lived in its nature. In view of this, diversion and illicit use ofSuboxone has frequently been reported, especially in hidden populationssuch as incarcerated and active drug abusers (see, for example, Alho etal, Drug and Alcohol Dependence, 88, 75 (2007), Monte et al, Journal ofAddictive Diseases, 28, 226 (2009), Stimmel, ibid., 26, 1 (2007) andSmith et al, ibid., 26, 107, 2007). Indeed, a recent study of untreatedintravenous abusers in Finland revealed that 68% reported abuse ofSuboxone. Moreover, 66% of those that had abused the drug once admittedthat they had abused it at least once subsequently, or even regularlythereafter (see Ahlo et al, supra).

Further, Suboxone has also been reported to have several othersignificant limitations. For example, the tablets are large anddisintegrate slowly. The bioavailability of buprenorphine is alsosignificantly lower than for a sublingual solution (see Compton et al,Drug and Alcohol Dependence, 82, 25 (2006)). Moreover, the taste is notwell tolerated by all patients and the tablet has an unpleasant grittymouthfeel. A film-based product has recently been developed tocounteract these problems, but the film formulation also does notdissolve particularly quickly. Furthermore, a maximum of only two films(with doses of 2 mg and 8 mg of buprenorphine) may be administeredsimultaneously. Sequential administration is thus required for (commonlyadministered) doses in excess of 10 mg or 16 mg of buprenorphine,respectively.

There is thus a presently unmet clinical need for an abuse-resistantproduct for use in opioid addiction substitution therapy, but which doesnot possess the afore-mentioned limitations. In particular, if it werepossible to devise a formulation that was capable of significantlyincreasing the bioavailability of buprenorphine, it might be possible toreduce the amount of this active pharmaceutical ingredient, giving riseto less opioid in the formulation and so reducing the amount availablefor injection if diverted by way of intravenous abuse.

International patent applications WO 00/16751, WO 2004/067004, WO2006/103418 and WO 2008/068471 all disclose drug delivery systems forthe treatment of e.g. acute pain by sublingual administration, applyingan interactive mixture principle, in which the active ingredient inmicroparticulate form is adhered to the surfaces of larger carrierparticles in the presence of a bioadhesive and/or mucoadhesive promotingagent. WO 2008/068471 in particular discloses a formulation comprisingparticles of opioid agonist drug upon the surfaces of carrier particlescomprising an opioid antagonist, such as naloxone.

Prior art documents, including international patent applications WO03/005944, WO 02/067903, WO 2007/141328, WO 2010/132605, WO 01/30288 andUS patent application US 2009/0263476 A1 employ pH modifying agents topromote dissolution and/or absorption of active ingredients.

We have now found that, by applying a specific formulation principle toa combination of specific active ingredients, buprenorphine andnaloxone, we have provided a product with unexpected, significantlyimproved pharmaceutical and clinical properties.

According to a first aspect of the invention there is provided apharmaceutical composition comprising microparticles of apharmacologically-effective amount of buprenorphine, or apharmaceutically-acceptable salt thereof, in associative admixture withparticles comprising a weak acid, or particles comprising weakly-acidicbuffer forming materials. Such compositions are referred to hereinafteras “the compositions of the invention”.

It is preferred that the pharmaceutical compositions comprisingbuprenorphine, or a pharmaceutically-acceptable salt thereof, arepresented in admixture (e.g. in simple mixture) together with adisintegrant.

In this respect, there is further provided a pharmaceutical compositioncomprising:

-   -   (i) a composition of the invention as hereinbefore defined        (“Component (i)”); and    -   (ii) a disintegrant (hereinafter “Component (ii)”).        Compositions comprising Components (i) and (ii) are also        referred to together hereinafter as compositions of the        invention.

It is further preferred that the pharmaceutical compositions comprisingbuprenorphine, or a pharmaceutically-acceptable salt thereof, arepresented in admixture (e.g. in simple mixture) together with adisintegrant and naloxone.

In this respect, there is further provided a pharmaceutical compositioncomprising:

-   -   (a) a composition of the invention comprising Components (i)        and/or (ii) as hereinbefore defined; and    -   (b) particles of a pharmacologically-effective amount of        naloxone, or a pharmaceutically-acceptable salt thereof        (hereinafter “Component (iii)”).        Compositions comprising Component (iii) formulated together with        Components, (i) and/or (ii) are also referred to together        hereinafter as compositions of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Graph of plasma profile for buprenorphine according to Example2.

FIG. 2: Graph of plasma profile for norbuprenorphine according toExample 2.

FIG. 3: Graph of plasma profile for naloxone according to Example 2.

FIG. 4: Graph of pH study of placebo tablet according to Example 4.

FIG. 5: Graph of in vitro pH study according to Example 5.

FIG. 6: Graph of release of buprenorphine according to Example 5.

FIG. 7: Graph of release of naloxone according to Example 5.

FIG. 8: Graph of in vitro pH study of several formulations according toExample 9.

FIG. 9: Graph of release of buprenorphine according to Example 9.

DETAILED DESCRIPTION OF THE INVENTION

Buprenorphine and pharmaceutically-acceptable salts thereof arepresented in the compositions of the invention in the form ofmicroparticles. Naloxone and pharmaceutically-acceptable salts thereofmay also (e.g. preferably) be presented in compositions of the inventionin the form of microparticles. Microparticles preferably possess aweight based mean diameter, number based mean diameter and/or a volumebased mean diameter of between about 0.5 μm and about 15 μm, such asabout 1 μm and about 10 μm. As used herein, the term “weight based meandiameter” will be understood by the skilled person to include that theaverage particle size is characterised and defined from a particle sizedistribution by weight, i.e. a distribution where the existing fraction(relative amount) in each size class is defined as the weight fraction,as obtained by e.g. sieving (e.g. wet sieving). As used herein, the term“number based mean diameter” will be understood by the skilled person toinclude that the average particle size is characterised and defined froma particle size distribution by number, i.e. a distribution where theexisting fraction (relative amount) in each size class is defined as thenumber fraction, as measured by e.g. microscopy. As used herein, theterm “volume based mean diameter” will be understood by the skilledperson to include that the average particle size is characterised anddefined from a particle size distribution by volume, i.e. a distributionwhere the existing fraction (relative amount) in each size class isdefined as the volume fraction, as measured by e.g. laser diffraction.

Microparticles of active ingredients may be prepared by standardmicronisation techniques, such as grinding, jet milling, dry milling,wet milling, precipitation, etc. An air elutriation process may beutilised subsequently to prepare specific size fractions, if required.

Preferred salts of buprenorphine and naloxone include hydrochloridesalts.

Buprenorphine and pharmaceutically-acceptable salts thereof areformulated together in associative admixture with particles of a weakacid, or with particles of weakly-acidic buffer forming materials, toprovide compositions of the invention (or Component (i) of compositionsof the invention).

Weakly acidic materials that may be mentioned include those that, whenprovided in a composition of the invention, enable the provision whenthe composition is dissolved in water and/or saliva (e.g. at the site ofadministration of compositions of the invention) of a pH of betweenabout 4.0 and about 6.5 (e.g. about 6.25), and are present in asufficient amount to enable the maintenance of pH within this range foran appropriate length of time (e.g. about 30 seconds, such as about 1minute) to about 3 minutes (e.g. about 2 minutes, such as about 1.5minutes) to facilitate dissolution of, particularly, the buprenorphinemicroparticles, and/or absorption of buprenorphine across the sublingualmucosa thereafter. For the purpose of this invention, the term includessubstances that are safe for use in mammals, and includes weak acids,weak acid derivatives and other chemicals that convert to weak acids invivo (e.g. precursors that convert to acids in vivo, by for examplebeing sequentially activated in accordance with properties of the localenvironment). Typical pKas of weak acids are in the range of betweenabout −1.5 (e.g. about −1.74) and about 16 (e.g. about 15.74) (e.g. seeVollhardt, Organic Chemistry (1987). A preferred range is between about1 and about 10. More preferably, the weakly acidic material comprises aweak acid that is safe for human consumption, for example a food acid,such as malic acid, fumaric acid, adipic acid, succinic acid, lacticacid, acetic acid, oxalic acid, maleic acid, ammonium chloride,preferably tartaric acid, and more preferably citric acid, or acombination of such acids. The skilled person will appreciate that, whenweak acids are employed which are not solids (and therefore notparticulate) at or around room temperature and atmospheric pressure,they may be adsorbed into a particulate carrier material (such ascolloidal silica) in order to provide particles comprising the weaklyacidic material.

Weakly-acidic buffer forming materials include materials that, whenprovided in a composition of the invention, provide a weakly acidicbuffer system when the composition is dissolved in water and/or saliva(e.g. at the site of administration of compositions of the invention),enabling the provision of a pH of between about 4.0 and about 6.5 (e.g.about 6.25), and are present in a sufficient amount to enable themaintenance of pH within this range for an appropriate length of time(e.g. about 30 seconds, such as about 1 minute) to about 3 minutes (e.g.about 2 minutes, such as about 1.5 minutes) to facilitate dissolutionof, particularly, the buprenorphine microparticles, and/or absorption ofbuprenorphine across the sublingual mucosa thereafter. Buffer formingmaterials thus include combinations of weak acid and salt of weak acid,such as combinations of the aforementioned acids with alkaline salts ofthose acids, including sodium citrate, potassium citrate, sodiumtartrate, potassium tartrate and the like. Preferred buffer formingmaterials are citric acid and sodium citrate. The skilled person willappreciate that, when materials are employed which are not solids (andtherefore not particulate) at or around room temperature and atmosphericpressure, they may be adsorbed into a particulate carrier material (suchas colloidal silica) in order to provide particles comprising theweakly-acidic buffer forming materials.

Suitable particles sizes of weakly acidic, or weakly-acidic bufferforming, materials are in the range about 1 μm and about 1000 μm (e.g.about 800 μm, such as about 750 μm), and preferably between about 40(such as about 50 μm) and about 600 μm. Suitable amounts of weaklyacidic materials that enable the maintenance of pH within theaforementioned ranges after oral administration as hereinbeforedescribed are in the range of at least about 1% to about 10% by weightof the total formulation. Suitable total amounts of weakly-acidic bufferforming materials that enable the maintenance of pH within theaforementioned ranges after oral administration as hereinbeforedescribed are in the range of at least about 1% to about 15% by weightof the total formulation.

The disintegrant or “disintegrating agent” that may be employed as, oras part of, Component (ii) in compositions of the invention may bedefined as any material that is capable of accelerating to a measurabledegree the disintegration/dispersion of a composition of the invention.The disintegrant may thus provide for an in vitro disintegration time ofabout 30 seconds or less, as measured according to e.g. the standardUnited States Pharmacopeia (USP) disintegration test method (see FDAGuidance for Industry: Orally Disintegrating Tablets; December 2008).This may be achieved, for example, by the material being capable ofswelling, wicking and/or deformation when placed in contact with waterand/or mucous (e.g. saliva), thus causing tablet formulations todisintegrate when so wetted.

Suitable disintegrants (as defined in, for example, Rowe et al, Handbookof Pharmaceutical Excipients, 6^(th) ed. (2009)) include cellulosederivatives such as hydroxypropyl cellulose (HPC), low substituted HPC,methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulosecalcium, carboxymethyl cellulose sodium, microcrystalline cellulose,modified cellulose gum; starch derivatives such as moderatelycross-linked starch, modified starch, hydroxylpropyl starch andpregelatinized starch; and other disintegrants such as calcium alginate,sodium alginate, alginic acid, chitosan, colloidal silicon dioxide,docusate sodium, guar gum, magnesium aluminium silicate, polacrilinpotassium and polyvinylpyrrolidone. Combinations of two or moredisintegrants may be used.

Preferred disintegrants include so-called “superdisintergrants” (asdefined in, for example, Mohanachandran et al, International Journal ofPharmaceutical Sciences Review and Research, 6, 105 (2011)), such ascross-linked polyvinylpyrrolidone, sodium starch glycolate andcroscarmellose sodium. Combinations of two or more superdisintegrantsmay be used.

Disintegrants may also be combined with superdisintegrants incompositions of the invention.

Disintegrants and/or superdisintegrants are preferably employed in an(e.g. total) amount of between 0.5 and 15% by weight based upon thetotal weight of a composition. A preferred range is from 1 to 8%, suchas from about 2 to about 7% (e.g. about 5%, such as about 4%) by weight.

Compositions of the invention may be formulated together (along with anyother materials that may be present) by standard simple mixingtechniques or by way of granulation.

Granules may be prepared by a process of dry granulation, wetgranulation, melt granulation, thermoplastic pelletising, spraygranulation or extrusion/spheronisation.

Wet granulation techniques are well known to those skilled in the artand include any technique involving the massing of a mix of dry primarypowder particles using a granulating fluid, which fluid comprises avolatile, inert solvent, such as water, ethanol or isopropanol, eitheralone or in combination, and optionally in the presence of a binder orbinding agent. The technique may involve forcing a wet mass through asieve to produce wet granules which are then dried, preferably to a losson drying of less than about 3% by weight.

Dry granulation techniques are also well known to those skilled in theart and include any technique in which primary powder particles areaggregated under high pressure, including slugging and rollercompaction, for example as described hereinafter.

Melt granulation will be known by those skilled in the art to includeany technique in which granules are obtained through the addition of amolten binder, or a solid binder which melts during the process. Aftergranulation, the binder solidifies at room temperature. Thermoplasticpelletising will be known to be similar to melt granulation, but inwhich plastic properties of the binder are employed. In both processes,the agglomerates (granules) obtained comprise a matrix structure.

Spray granulation will be known by those skilled in the art to includeany technique involving the drying of liquids (solutions, suspensions,melts) while simultaneously building up granulates in a fluid bed. Theterm thus includes processes in which foreign seeds (germs) are providedupon which granules are built up, as well as those in which inherentseeds (germs) form in the fluid bed due to abrasion and/or fracture, inaddition to any spray coating granulation technique generally. Thesprayed liquid coats the germs and assists further agglomeration ofparticles. It is then dried to form granules in the form of a matrix.

Extrusion/spheronisation will be well known to those skilled in the artto include any process involving the dry mixing of ingredients, wetmassing along with a binder, extruding, spheronising the extrudate intospheroids of uniform size, and drying.

In particular, microparticles of buprenorphine or salt thereof andparticles of weakly acidic, weakly-acidic buffer forming, materials arepresented in associative admixture with each other in compositions ofthe invention. By “associative admixture” we mean that whether or notComponent (i) is subsequently formulated along with Components (ii) and(iii) as hereinbefore defined, some form of mixing step (simple mixing,granulation as described hereinbefore, or otherwise) takes place asbetween the buprenorphine/salt microparticles and particles of weaklyacidic, weakly-acidic buffer forming, materials, rendering them inintimate contact with each other.

For the avoidance of doubt, by “intimate contact”, we include thatmicroparticles of buprenorphine or salt thereof, and particles of weaklyacidic, weakly-acidic buffer forming, materials, are presented incompositions of the invention in any form in which they are, at least inpart, in intimate contact with each other. This includes the possibilityof the inclusion of quickly dissolving coatings on one or other, orboth, sets of particles.

In this respect, Component (i) is preferably presented as, or as partof, a composition of the invention in the form of a interactive mixturecomprising at least one population of carrier particles upon thesurfaces of which are presented (e.g. adhered) microparticles ofbuprenorphine or a pharmaceutically acceptable salt thereof.

The term “interactive” mixture will be understood by those skilled inthe art to include the term “ordered” mixture, and to denote a mixturein which particles do not appear as single units, as in random mixtures,but rather where smaller particles (e.g. microparticles of, for example,buprenorphine) are attached to (i.e. adhered to or associated with) thesurfaces of larger carrier particles. Such mixtures are characterised byinteractive forces (for example van der Waals forces, electrostatic orCoulomb forces, and/or hydrogen bonding) between carrier andsurface-associated particles (see, for example, Staniforth, PowderTechnol., 45, 75 (1985)). In final mixtures, and compositions comprisingsuch mixtures, the interactive forces need to be strong enough to keepthe adherent particles at the carrier surface.

When interactive mixtures are employed as the formulation principle bywhich the particulate Component (i) is presented in a composition of theinvention, these are made, preferably, with carrier particles that areof a size (weight and/or volume based average or mean diameter, videsupra) that is between about 30 μm and about 1000 μm (e.g. about 800 μm,such as about 750 μm), and preferably between about 40 (such as about 50μm) and about 600 μm.

Carrier particles may comprise pharmaceutically-acceptable substancesthat are soluble in water, such as carbohydrates, e.g. sugars, such aslactose, and sugar alcohols, such as mannitol, sorbitol and xylitol;pharmaceutically-acceptable inorganic salts, such as sodium chloride.Water soluble carrier particles may also comprise the weakly acidic,and/or weakly acidic buffer forming materials, mentioned hereinbefore(such as citric acid and/or sodium citrate). Alternatively, carrierparticles may comprise pharmaceutically-acceptable substances that areinsoluble or sparingly soluble in water, such as dicalcium phosphateanhydrate, dicalcium phosphate dihydrate, tricalcium phosphate, calciumcarbonate, and barium sulphate; starch and pre-gelatinised starch;bioadhesive and mucoadhesive materials, such as crosslinkedpolyvinylpyrrolidone and croscarmellose sodium; and other polymers, suchas microcrystalline cellulose, cellulose and; or mixtures thereof.

By “soluble in water” we include that the material has a solubility inwater that is greater than 33.3 mg/mL at atmospheric pressure (e.g. 1bar) and room temperature (e.g. 21° C.). On the other hand, the term“sparingly soluble or insoluble in water” includes materials that have asolubility in water that is less than 33.3 mg/mL under the sameconditions. Preferred soluble carrier particle materials include sugaralcohols, such as sorbitol, xylitol and particularly mannitol. Preferredsparingly water-soluble or water-insoluble carrier particle materialsinclude cellulose and starches, such as microcrystalline cellulose.

It is preferred that buprenorphine or pharmaceutically acceptable saltthereof is presented on the surfaces of water-soluble carrier particles.

In this respect, as stated above, weakly acidic materials, and/orweakly-acidic buffer forming materials, may also function aswater-soluble carrier particle materials. Therefore, the associatedadmixture of such materials with buprenorphine/salt thereof may mean theformer comprise carrier particles upon which microparticles of thelatter are presented. In such cases, such materials may be presented atleast as further water-soluble carrier particles, in addition to thepresence of other water-soluble carrier particles, upon the surfaces ofboth of which are presented burprenorphine microparticles.

When carrier particles comprise such weakly acidic/buffer formingmaterials, composites of such materials with other water-soluble carrierparticle materials (such as those described hereinbefore) may beprovided. Such materials may be prepared by direct compression orgranulation, for example. Alternatively, carrier particles may consistessentially of a weakly acidic material and/or one or more materialsthat, when dissolved in saliva, give rise to a weakly acidic buffersystem. By “consisting essentially” of such materials, we mean that,excluding the possible presence of water (vide infra), the carrierparticles comprise at least about 95%, such as at least about 98%, morepreferably greater than about 99%, and particularly at least about 99.5%by weight (based on the total weight of the carrier particle) of suchmaterials. These percentages exclude the presence of trace amounts ofwater (e.g. crystal water or water bound to external surfaces ofmaterials), and/or any impurities that may be present in such materials,which impurities may arise following the production of such materials,either by a commercial or non-commercial third party supplier, or by askilled person making a composition of the invention.

Alternatively (and/or in addition), in Component (i), particles ofweakly acidic material, and/or of weakly-acidic buffer formingmaterials, may be presented, at least in part, upon the surfaces of,and/or between, carrier particles. In such cases, suitable particlesizes of such materials are as presented herein for active ingredientsand/or disintegrants.

When employed in compositions of the invention, Components (ii) and(iii) are preferably formulated together, for example to form particlescomprising naloxone or salt thereof and the disintegrant, prior tomixing with Component (i). Alternatively, particles of weakly acidicmaterial, and/or of weakly-acidic buffer forming materials, may beformulated along with Components (ii) and/or (iii) prior to mixing withbuprenorphine microparticles, which latter microparticles may bepresented in the form of interactive mixtures with carrier particles ashereinbefore described. Weakly acidic, and/or weakly-acidic bufferforming, materials may thus be formulated in associative admixture withbuprenorphine microparticles (as hereinbefore defined) in this way.

Furthermore, in Component (iii), particles of naloxone, orpharmaceutically-acceptable salts thereof, may also be presented uponthe surfaces of, and/or between, carrier particles in compositions ofthe invention, but this is not essential. Such carrier particles may bewater-soluble (as hereinbefore defined), or may (preferably) bewater-insoluble/sparingly soluble carrier particles.

Disintegrant and/or superdisintegrant materials, may also be presented,at least in part, as particles upon the surfaces of, and/or between,carrier particles, which may or may not also carry naloxone or saltthereof. If employed in particulate form, particles of disintegrantsand/or superdisintegrants may be presented with a particle size (weightand/or volume based average or mean diameter, vide supra) of betweenabout 0.1 and about 100 μm (e.g. about 1 and about 50 μm).

Alternatively, disintegrants and/or superdisintegrants may also bepresent as a constituent in composite excipients. Composite excipientsmay be defined as co-processed excipient mixtures. Examples of compositeexcipients comprising superdisintegrants are Parteck® ODT, Ludipress®and Prosolv® EASYtab.

Bio/mucoadhesive materials may also be presented in compositions of theinvention. Such materials may be presented upon (e.g. adhered to) thesurfaces of carrier particles when components of compositions of theinvention are presented in the form of interactive mixtures.

Compositions of the invention may be employed in the treatment of opioiddependency and/or addiction as described hereinbefore, for example insubstitution therapy programs. Opioid dependency and/or addiction may bedefined in numerous ways (see, for example,www.who.int/substance_abuse/terminology/definition1), but may becharacterized for example by physiological, behavioural, and cognitivephenomena wherein the use of a substance or a class of substances takeson a much higher priority for a given individual than other behavioursthat once had greater value, and/or characterised by a desire (oftenstrong, and sometimes overpowering) to take opioids and/or opiates(which may or may not have been medically prescribed). It isparticularly preferred that compositions of the invention comprisingnaloxone are used in the treatment of opioid dependency and/oraddiction.

Buprenorphine is a partial agonist at the μ-opioid receptor and anantagonist at the κ-opioid receptor. It has high binding affinity atboth receptors and competes with other agonists, such as methadone,heroin (diamorphine) and morphine, at the μ-opioid receptor. Opioidagonist effects of buprenorphine are less than the maximal effects ofother, “full” opioid agonists, such as morphine, and are limited by a“ceiling” effect. The drug thus produces a lower degree of physicaldependence than other opioid agonists, such as heroin, morphine ormethadone and is therefore particularly useful in substitution therapy.

The term “pharmacologically effective amount” refers to an amount of anactive ingredient, which is capable of conferring a desired therapeuticeffect on a treated patient, whether administered alone or incombination with another active ingredient. Such an effect may beobjective (i.e. measurable by some test or marker) or subjective (i.e.the subject gives an indication of, or feels, an effect).

Thus, appropriate pharmacologically effective amounts of buprenorphine(or salt thereof) include those that are capable of producing, and/orcontributing to the production of, the desired therapeutic effect,namely decreased opioid and/or opiate craving and/or decreased illicitdrug use, when administered transmucosally, whereas appropriatepharmacologically effective amounts of naloxone (or salt thereof) whenemployed must be sufficient so as not to compete with theabove-mentioned pharmacological effect of the buprenorphine present inthe composition of the invention upon transmucosal administration, butto antagonize the effect of the buprenorphine and precipitate withdrawalsymptoms if an attempt is made by an opioid-addicted individual toinject a composition of the invention.

The amounts of active ingredients that may be employed in compositionsof the invention may thus be determined by the skilled person, inrelation to what will be most suitable for an individual patient. Thisis likely to vary with the route of administration, the type andseverity of the condition that is to be treated, as well as the age,weight, sex, renal function, hepatic function and response of theparticular patient to be treated.

The total amount of buprenorphine/salt thereof that may be employed in acomposition of the invention may be in the range of about 0.1%, such asabout 1%, to about 20%, such as about 10%, by weight based upon thetotal weight of the composition. The amount of this active ingredientmay also be expressed as the amount in a unit dosage form (e.g. atablet). In such a case, the amount of buprenorphine/salt that may bepresent may be sufficient to provide a dose of buprenorphine (calculatedas the free base) per unit dosage form that is in the range of betweenabout 0.1 mg, such as about 1 mg and about 50, for example about 30,such as about 20 mg (e.g. about 15 mg, e.g. about 12 mg, such as about10 mg). Preferred ranges for the treatment of pain are about 0.1 mg toabout 4 mg. Preferred ranges for substitution therapy are about 0.5 mgto about 50 mg, such as about 0.75 mg, (e.g. about 1 mg) to about 12 mg,such as about 10 mg (e.g. about 7 mg). Individual buprenorphine dosesper tablet that may be mentioned include about 11.4 mg, about 8.6 mg,about 5.7 mg, about 2.9 mg and about 1.4 mg.

When employed, the total amount of naloxone/salt thereof that may beemployed in a composition of the invention may be in the range about0.125%, such as about 0.25% to about 5%, such as about 2.5%, by weightbased upon the total weight of the composition. The amount of thisactive ingredient may also be expressed as the amount in a unit dosageform (e.g. a tablet). In such a case, the amount of naloxone/salt thatmay be present may be sufficient to provide a dose of naloxone(calculated as the free base) per unit dosage form that is in the rangeof between about 0.125 mg and about 12.5 mg, such as about 0.19 mg (e.g.about 0.25 mg) to about 3 mg, such as about 2.5 mg (e.g. about 1.75 mg).Individual naloxone doses per tablet that may be mentioned include about2.9 mg, about 2.2 mg, about 1.4 mg, about 0.7 mg and about 0.4 mg.

Although, for compositions of the invention containing naloxone, it ispreferred that the dose ratio of buprenorphine:naloxone is maintained atabout 4:1, the above-mentioned dosages are exemplary of the averagecase; there can, of course, be individual instances where higher orlower dosage ranges are merited, and such are within the scope of thisinvention.

Compositions of the invention, once prepared, are preferably directlycompressed/compacted into unit dosage forms (e.g. tablets) foradministration to mammalian (e.g. human) patients, for example asdescribed hereinafter.

Compositions of the invention may be in the form of powders or, morepreferably, tablets for e.g. sublingual administration. Tablets may alsocomprise a binder. A binder may be defined as a material that is capableof acting as a bond formation enhancer, facilitating the compression ofthe powder mass into coherent compacts. Suitable binders includecellulose gum and microcrystalline cellulose. If present, binder ispreferably employed in an amount of between 0.5 and 20% by weight basedupon the total weight of the tablet formulation. A preferred range isfrom 1 to 15%, such as from about 2.0 to about 12% (e.g. about 10%) byweight.

Suitable further additives and/or excipients that may be employed incompositions of the invention, in particular those in the form oftablets for e.g. sublingual administration may comprise:

-   -   (a) lubricants (such as magnesium stearate or, preferably,        sodium stearyl fumarate);    -   (b) flavourings (e.g. lemon, peppermint powder or, preferably,        menthol), sweeteners (e.g. neohesperidin, acesulfame K or,        preferably, sucralose) and dyestuffs;    -   (c) antioxidants, which may be naturally occurring or otherwise        (e.g. butylated hydroxytoluene (BHT), vitamin C, vitamin E,        β-carotene, uric acid, uniquion, superoxide dismutase (SOD),        glutathione peroxidase or peroxidase catalase); and/or    -   (d) other ingredients, such as carrier agents, preservatives and        gliding agents (e.g. colloidal silica).

Compositions of the invention may be prepared by standard techniques,and using standard equipment, known to the skilled person.

When presented in the form of interactive mixtures, particles of e.g.buprenorphine/salt may be dry mixed with relevant carrier particles overa period of time that is sufficiently long to enable appropriate amountsof respective active ingredients to adhere to the surface of the carrierparticles. This may also apply to other active ingredients and/orexcipients defined hereinbefore.

The skilled person will appreciate that, in order to obtain a dry powderformulation in the form of an interactive mixture, larger carrierparticles must be able to exert enough force to break up agglomerates ofsmaller particles. This ability will primarily be determined by particledensity, surface roughness, shape, flowability and, particularly,relative particle sizes.

Standard mixing equipment may be used in this regard. The mixing timeperiod is likely to vary according to the equipment used, and theskilled person will have no difficulty in determining by routineexperimentation a suitable mixing time for a given combination of activeingredient and carrier particle material(s).

Interactive mixtures may also be provided using techniques other thandry mixing, which techniques will be well known to those skilled in theart.

Other ingredients may alternatively be incorporated by standard mixingor other formulation principles.

The compositions of the invention may be administered transmucosally,such as buccally, rectally, nasally or preferably sublingually by way ofappropriate dosing means known to the skilled person. A sublingualtablet may be placed under the tongue, and the active ingredientsabsorbed through the surrounding mucous membranes.

In this respect, the compositions of the invention may be incorporatedinto various kinds of pharmaceutical preparations intended fortransmucosal (e.g. sublingual) administration using standard techniques(see, for example, Lachman et al, “The Theory and Practice of IndustrialPharmacy”, Lea & Febiger, 3^(rd) edition (1986) and “Remington: TheScience and Practice of Pharmacy”, Gennaro (ed.), Philadelphia Collegeof Pharmacy & Sciences, 19^(th) edition (1995)).

Pharmaceutical preparations for sublingual administration may beobtained by combining compositions of the invention with conventionalpharmaceutical additives and/or excipients used in the art for suchpreparations, and thereafter preferably directly compressed/compactedinto unit dosage forms (e.g. tablets). (See, for example, PharmaceuticalDosage Forms: Tablets. Volume 1, 2^(nd) Edition, Lieberman et al (eds.),Marcel Dekker, New York and Basel (1989) p. 354-356 and the documentscited therein.) Suitable compacting equipment includes standardtabletting machines, such as the Kilian SP300, the Korsch EK0, theKorsch XP1, the Korsch XL100 or the Korsch PharmaPress 800.

Suitable final sublingual tablet weights are in the range of about 30 toabout 400 mg, such as about 40 (e.g. about 50) to about 300 mg (e.g.about 250 mg, such as about 200 mg), for example about 50 (e.g. about60) to 180 mg, more preferably between about 60 (e.g. about 70) andabout 160 mg. Suitable final tablet diameters are in the range of about3 to about 12 mm, for example about 4 to about 10 mm, and morepreferably about 5 to about 9 mm. Suitable final tablet thicknesses arein the range of about 0.5 mm to about 4 mm, such as about 1.5 mm toabout 3 mm. Various tablet shapes are possible (e.g. circular,triangular, square, diamond, polygon or oval). Suitable tablethardnesses include crushing strengths in the range of about 10N to about100N, for example about 15N to about 50N (depending on the size and/orweight of the tablet), according to US Pharmacopoeia method <1217>.

Irrespective of the foregoing, compositions of the invention comprisingdisintegrants (or other excipients that function by swelling) should beessentially free (e.g. less than about 20% by weight based on the totalweight of the formulation) of water. It will be evident to the skilledperson that “premature” hydration will dramatically decrease theperformance of a tablet formulation in use and may result in prematuredissolution of active ingredients.

Wherever the word “about” is employed herein in the context ofdimensions (e.g. tablet sizes and weights, particle sizes etc.), surfacecoverage (e.g. of carrier particles by particles of active ingredients),amounts (e.g. relative amounts of individual constituents in acomposition or a component of a composition and absolute doses(including ratios) of active ingredients), temperatures, pressures,times, pH values, concentrations, it will be appreciated that suchvariables are approximate and as such may vary by ±10%, for example ±5%and preferably ±2% (e.g. ±1%) from the numbers specified herein.Wherever the word “about” is employed herein in the context ofpharmacokinetic properties (C_(max), t_(max), AUCs),etc., it will beappreciated that such variables are approximate and as such may vary by±15%, such as ±10%.

Compositions of the invention may be administered by way of appropriatedosing means known to the skilled person. For example, a sublingualtablet may be placed under the tongue, and the active ingredientsabsorbed through the surrounding mucous membrane.

We have found that compositions of the invention surprisingly give riseto significantly improved bioavailability for buprenorphine whencompared to prior art, commercially-available formulations. This meansthat formulations with lower single doses of buprenorphine may beadministered by way of compositions of the invention, so reducing the“street value” of a single tablet when it comprises a composition of theinvention, with more than one such tablet being required to give thesame effect when illicitly administered parenterally (i.e. in “street”terms, the same “fix”). This means that compositions of the inventionare less likely to be abused than prior art, commercially-availableformulations (see Comer et al, Addiction, 105, 709-718 (2010)).

Additionally, we have found that compositions of the inventioncomprising naloxone also surprisingly give rise to significantly (andsimultaneously with buprenorphone) improved bioavailability for naloxonewhen compared to prior art, commercially-available formulations.

Compositions of the invention comprising naloxone thus surprisingly giverise to similar, almost parallel, degrees of improved bioavailabilityfor both buprenorphine and naloxone, which means that the “optimal”ratio of buprenorphine to naloxone, which has been arrived at to reduceabuse potential (see, for example, Mendelson and Jones, Drug and AlcoholDependence, 70, 829 (2003)), may be maintained, and doses of both activeingredients therefore lowered by an equivalent degree to preserve thesame ratio.

According to a further aspect of the invention, there is provided amethod of treating opioid dependency and/or addiction in a human,

-   -   which method comprises sublingual administration to a human        patient suffering from opioid dependency and/or addiction of    -   at least one unit dose of a pharmaceutical composition (e.g. a        tablet) comprising buprenorphine or a pharmaceutically        acceptable salt thereof, in combination with naloxone or a        pharmaceutically acceptable salt thereof, in about a 4:1        buprenorphine:naloxone dose ratio (calculated as free bases),    -   wherein said unit dose composition comprises a dose of        buprenorphine, which is about 75% of that of a random mixture        compressed (RMC) tablet comprising buprenorphine, and    -   which method achieves, after an initial dose in any given        treatment program, a plasma-concentration time profile for        buprenorphine (and/or naloxone) that is essentially equivalent        to that/those exhibited by such RMC tablets.

“RMC tablets” include, but are not limited to, thecommercially-available tablet product Suboxone® (NDA No. 20-733,approval date October 8^(th), 2002; buprenorphine strength 2 mg (ProductNo. 001; actual weight about 100 mg) and 8 mg (Product No. 002; actualweight about 400 mg)). The 8 mg tablets (at least) have a mean crushingstrength (US Pharmacopeia method <1217>) of about 127 N. RMC tabletstrengths are thus in the range of about 80 to about 180 N. RMC tabletsare formed by compression of a random mixture, prepared by wetgranulation of a standard mixture comprising buprenorphinehydrochloride, naloxone hydrochloride dihydrate, lactose monohydrate,mannitol, maize starch, povidone K30, citric acid (anhydrous granular),sodium citrate, natural lemon and lime flavour, acesulfame potassium andmagnesium stearate.

By “a plasma-concentration time profile for buprenorphine and/ornaloxone that is essentially equivalent to that/those exhibited by suchRMC tablets”, we include that, after an initial dose in any giventreatment program, one or more of:

-   -   (i) the maximum plasma concentration (C_(max)); and/or    -   (ii) the time to maximum plasma concentration (t_(max)); and/or    -   (iii) the total area under the plasma concentration-time curve        from time zero to the time of the last measured plasma        concentration (AUC_(t)); and/or    -   (iv) the area under the plasma concentration-time curve from        time zero to the last concentration extrapolated to infinity        based on the elimination rate constant (AUC_(inf)),        as measured by standard pharmacokinetic monitoring means, e.g.        as described in Example 2 hereinafter, for naloxone and/or, more        preferably, for buprenorphine, is between about 80% and about        125% of the corresponding values obtained for the aforementioned        RMC tablets.

Thus, after an initial dose in any given treatment program, for tabletscomprising a dose of buprenorphine that is about 75% of a RMC tabletcomprising 8 mg of buprenorphine may present:

-   -   (i) a C_(max) of between about 3.0 ng/mL and about 5.6 (such as        about 4.5) ng/mL; and/or    -   (ii) a t_(max) that is less than about 3 hours, preferably less        than about 2 hours; and/or    -   (iii) an AUC_(inf) that is about 25 ng·h/mL to about 40 ng·h/mL,        such as about 28 ng·h/mL to about 36 ng·h/mL,        for buprenorphine; and/or    -   (a) a C_(max) of between about 150 pg/mL and about 300 (such as        about 250) pg/mL; and/or    -   (b) a t_(max) that is less than about 1 hour,        for naloxone.

Thus, after an initial dose in any given treatment program, for tabletscomprising a dose of buprenorphine that is about 75% of a RMC tabletcomprising 8 mg of buprenorphine may present:

According to a further aspect of the invention, there is provided amethod of treating opioid dependency and/or addiction in a human,

-   -   which method comprises sublingual administration to a human        patient suffering from opioid dependency and/or addiction of    -   at least one unit dose of a pharmaceutical composition (e.g. a        tablet) comprising buprenorphine or a pharmaceutically        acceptable salt thereof, in combination with naloxone or a        pharmaceutically acceptable salt thereof, in about a 4:1        buprenorphine:naloxone dose ratio (calculated as free bases),    -   wherein said unit dose composition comprises a dose of        buprenorphine, which is about 75% of that of a RMC tablet as        hereinbefore defined, and    -   which method achieves after an initial dose in any given        treatment program a mean relative bioavailability compared to        such RMC tablets that is:        -   (A) about 1.2 to about 1.6 for buprenorphine; and/or        -   (B) about 1.2 to about 2.0 for naloxone.

According to a further aspect of the invention, there is provided amethod of treating opioid dependency and/or addiction in a human, whichmethod comprises sublingual administration to a human patient sufferingfrom opioid dependency and/or addiction of at least one unit dose of apharmaceutical composition (e.g. a tablet) comprising buprenorphine or apharmaceutically acceptable salt thereof, in combination with naloxoneor a pharmaceutically acceptable salt thereof, wherein said tabletcomprises a dose of buprenorphine or salt thereof, which is about 6 mgor about 1.5 mg, and the buprenorphine:naloxone dose ratio is about 4:1(calculated as the free base).

Compositions of the invention may also give rise to a lowernorbuprenorphine:buprenorphine ratio in plasma when compared to priorart, commercially-available formulations. A lower norbuprenorphine tobuprenorphine ratio is also seen after sublingual administration of anethanol solution compared to a tablet formulation (see Harris et al,Clin. Pharmacokinet., 43, 329 (2004)) as dose is increased, suggestingthat less buprenorphine is being swallowed. In addition, lessnorbuprenorphine is found in the plasma after parenteral administrationcompared to sublingual administration (Sigmon et al, Addiction, 101, 420(2005)), further supporting the notion that norbuprenorphine is formedfrom swallowed buprenorphine by first pass metabolism through the liver.Thus, the lower norbuprenorphine:buprenorphine ratio reported herein maybe reflective of the fact that more buprenorphine is absorbed over thesublingual mucosa (and so less is swallowed) than with prior art,commercially available (e.g. RMC tablet) formulations. There may also bebenefits from the reduction of the norbuprenorphine:buprenorphine ratioper se, such as reduced respiratory depression (see Megarbane et al,Toxicology and Applied Phamacology, 212, 256 (2006)).

According to a further aspect of the invention, there is furtherprovided a method of treating opioid dependency and/or addiction in ahuman, which method comprises sublingual administration of apharmaceutical composition comprising buprenorphine or apharmaceutically acceptable salt thereof, in combination with naloxoneor a pharmaceutically acceptable salt thereof, in about a 4:1buprenorphine:naloxone dose ratio (calculated as the free base), whereinsaid composition comprises a dose of buprenorphine which is about 75% ofthat of a RMC tablet as hereinbefore defined, to a human patientsuffering from opioid dependency and/or addiction, wherein saidformulation achieves after an initial dose in any given treatmentprogram a ratio of norbuprenorphine/buprenorphine concentrations inplasma of less than about 0.8 based upon AUC₂₄.

Such methods may comprise administration of a composition of theinvention as defined herein.

By “any given treatment program”, we mean any course of treatment of apatient with a composition of the invention.

Without being limited by theory, it is understood that the compositionsof the invention give rise to such surprisingly increasedbioavailability when compared to prior art, commercially-availableformulations, e.g. RMC tablets, such as Suboxone, because of a pH-timingeffect, in which pH is lowered as hereinbefore described for a shortperiod of time (e.g. between about 1 and about 3 minutes) aftersublingual administration, resulting in improved and/or more rapiddissolution of microparticles of burprenorphine. Although suchdissolution might be expected to be improved by decreasing pH, what iscompletely unexpected is that the degree of absorption across thesublingual mucosa does not appear to decrease. One would expect thatlowering local pH would give rise to the presence of more burprenorphinein the ionized state at the site of absorption, which would in turn beexpected to decrease the degree of absorption across the sublingualmucosa. The fact that the bioavailability is better per unit dose ofbuprenorphine for compositions of the invention than it is for prior artcompositions is indeed remarkable.

According to a further aspect of the invention, there is provided apharmaceutical composition comprising microparticles of buprenorphine ora pharmaceutically acceptable salt thereof, and particles of a weak acidor particles of weakly acidic buffer forming materials, characterized inthat the composition exhibits, in an in vitro small-volume funneldissolution method, for example as described in Example 5 hereinafter:

-   -   a) a pH drop of about 0.5 to about 5 pH units;    -   b) a maximum pH drop within about 1 minute of the start of the        method; and    -   c) a return to the initial pH (±0.5) within about 3 minutes.

According to a still further aspect of the invention, there is provideda pharmaceutical composition comprising microparticles of buprenorphineor a pharmaceutically acceptable salt thereof, and particles of a weakacid or particles of weakly acidic buffer forming materials,characterized in that the composition enables the provision (at the siteof administration) of a pH of between about 4.0 and about 6.5 (e.g. lessthan about 6.25), and the maintenance of pH within this range for anappropriate length of time (e.g. about 30 seconds, such as about 1minute) to about 3 minutes (e.g. about 2 minutes, such as about 1.5minutes) to facilitate dissolution of, particularly, the buprenorphinemicroparticles, and/or absorption of buprenorphine across the sublingualmucosa thereafter.

Compositions of the invention comprising naloxone surprisingly give riseto similar, almost parallel, degrees of improved bioavailability forboth buprenorphine and naloxone, which means that the “optimal” ratio ofbuprenorphine to naloxone, which has been arrived at to reduce abusepotential (see, for example, Mendelson and Jones, Drug and AlcoholDependence, 70, 829 (2003)), may be maintained, and doses of both activeingredients therefore lowered by an equivalent degree to preserve thesame ratio.

The compositions of the invention are useful in the treatment of opioiddependency and/or addiction. Compositions of the invention may also beuseful in the treatment of pain (including mild, moderate and severepain).

According to three further aspects of the invention there are provided:

-   -   (i) a method of treatment of opioid dependency and/or addiction;    -   (ii) a method of treatment of pain; and    -   (iii) a method of treatment of both pain and opioid dependency        and/or addiction,        which methods comprise administration of a composition of the        invention to a person suffering from, or susceptible to, the        relevant conditions.

Compositions of the invention may also be administered in the inductionphase (i.e. the start-up) of buprenorphine therapy, whereinbuprenorphine is administered once an opioid-addicted individual hasabstained from using opioids for about 12-24 hours and is in the earlystages of opioid withdrawal.

According to a further aspect of the invention there is provided amethod of treatment of opioid dependency and/or addiction, which methodcomprises administration of a composition of the invention to anindividual that has abstained from using opioids for at least about 12hours and/or is in the early stages of opioid withdrawal.

By “treatment” of pain we include the therapeutic treatment, as well asthe symptomatic and palliative treatment of the condition. However, by“treatment” of opioid dependency and/or addiction, we further includethe prophylaxis, or the diagnosis of the relevant condition in additionto therapeutic, symptomatic and palliative treatment. This is because,by employing buprenorphine in the treatment of pain, compositions of theinvention may prevent the development of opioid dependency and/oraddiction.

The compositions of the invention enable the production of unit dosageforms that are easy and inexpensive to manufacture, and which enable therapid release and/or a rapid uptake of the active ingredients employedthrough the mucosa, such as the oral mucosa, thus enabling rapid reliefof symptoms, such as those described hereinbefore.

The compositions of the invention also have the advantage that, ifinjected by an opioid addict, they do not produce the euphoric effectsthat such an addict seeks and indeed induce opioid withdrawal symptoms.

Compositions of the invention may also have the advantage that they maybe prepared using established pharmaceutical processing methods andemploy materials that are approved for use in foods or pharmaceuticalsor of like regulatory status.

Compositions of the invention may also have the advantage that they maybe more efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, possess a better patient acceptability than, have abetter pharmacokinetic profile than, and/or have other usefulpharmacological, physical, or chemical properties over, pharmaceuticalcompositions known in the prior art, whether for use in the treatment ofopioid addiction or pain or otherwise.

EXAMPLES

The invention is illustrated by way of the following examples, withreference to the attached figures in which analyte concentration-timeplasma profiles are presented in linear scale plots for buprenorphine(FIG. 1), norbuprenorphine (FIG. 2) and naloxone (FIG. 3) followingsublingual administration of tablets comprising a composition of theinvention (diamonds) and the commercially-available comparator,Suboxone® (squares); FIG. 4 shows an in vivo sublingual pH profileobtained for a placebo composition (analogous to one prepared inaccordance with the invention); FIG. 5 shows comparative in vitro pHprofiles for composition of the invention versus Suboxone and othercomparators in a small-volume funnel dissolution test; FIGS. 6 and 7show release of buprenorphine and naloxone, respectively, from thecompositions referred to in FIG. 5; FIG. 8 shows comparative in vitro pHprofiles for compositions of the invention versus Suboxone and othercomparators in a small-volume funnel dissolution test; and FIG. 9 showrelease of buprenorphine from compositions referred to in FIG. 8.

Example 1

Buprenorphine/Naloxone Sublingual Tablets I

Naloxone hydrochloride dihydrate (Macfarlan Smith, Edinburgh, UK) andbuprenorphine hydrochloride (Macfarlan Smith, Edinburgh, UK) weremicronised using an air jet mill (Pilotmill-1/Food and Pharma Systems,Italy). The volume based mean particle size (diameter) of thebuprenorphine was 3.4 μm and of the naloxone was 4.6 μm.

9.15 g of the micronised naloxone hydrochloride dihydrate was mixedtogether with microcrystalline cellulose (47.50 g; Avicel™ PH102 (meanparticle size 100 μm), FMC Biopolymer, Cork, Ireland) and croscarmellosesodium (18.00 g; AcDiSol™, FMC Biopolymer) in a tumble blender (Turbula,WAG, Switzerland) for 40 hours.

32.40 g of the micronised buprenorphine hydrochloride was mixed togetherwith mannitol (314.20 g; Pearlitol™ 200SD, Roquette, Lestrem, France),sieved citric acid (15.00 g; fine granular 16/40 grade, DSM,Switzerland, Basel) and sieved (to avoid agglomeration) sodium citrate(48.75 g) Emprove™ cryst., Merck, Darmstadt, Germany) in a tumbleblender for 40 hours.

Menthol (5.00 g; Emprove™ cryst., Merck) was mortared until a finepowder was formed. This and also acesulfame potassium (5.00 g; SunettPharma D, Nutrinova, Kelsterbach, Germany) and anhydrous colloidalsilica (5.00 g; Aerosil™ 200 Pharma, Evonik Degussa, Hanau-Wolfgang,Germany) were added by sieving into the buprenorphine premix, togetherwith the naloxone premix, and the whole mixed together in a tumbleblender for 1 hour.

Sodium stearyl fumarate (10.00 g; Pruv™, JRS Pharma, Polanco, Spain) wasthen added by sieving into this mixture and mixing continued in thetumble blender for 5 minutes.

The final powder mixture was then compressed into tablets in a tabletmachine (Korsch XP1) equipped with 7 mm round, flat faced, radius-edgedpunches, to a tablet weight of 102 mg and a tablet crushing strength of35 N.

Example 2

Clinical Trial

The tablets of Example 1 were sublingually administered in anopen-label, 2-period crossover study with randomised treatment sequence.

The study comprised a screening visit conducted within 28 days prior tofirst treatment, two treatment periods each of 4 days length (Day −1 toDay 3) and a washout period of at least 10 days between treatmentperiods. During the treatment periods, subjects were admitted to theclinical unit on the morning prior to first dosing (Day −1) and remainedin the unit until the completion of Day 3 procedures. A follow-up visitwas carried out 5 to 10 days after completion of the secondInvestigational Medicinal Product (IMP) administration.

The IMPs were sublingual tablet prepared in accordance with Example 1 (6mg buprenorphine/1.5 mg naloxone; hereafter “formulation of theinvention”) and, as the reference product, Suboxone sublingual tablet (8mg buprenorphine/2 mg naloxone; Reckitt Benckiser Healthcare Ltd, Hull,UK). Treatment with formulation of the invention, or Suboxone (1 tablet)in alternate periods was open-label and was administered on Day 1 ineach treatment period.

Naltrexone tablets (Nalorex®, 50 mg, Bristol-Myers SquibbPharmaceuticals Ltd; Uxbridge, UK) were administered orally (one 50 mgtablet), at −24 to −16 hours, −1 hour (±5 minutes) and +24 hours (±1hour) in relation to administration of IMP, as a naltrexone block in thestudy (in order to alleviate opioid side effects during the study).

Eighteen healthy male volunteers aged between 18 and 50 years wereenrolled. These received both treatments and were evaluated. The meanage was 29.8 years and ages ranged from 19 to 49 years. All subjectswere male Caucasians. The mean weight was 78.16 kg and ranged from 63.0to 93.5 kg. The mean body mass index of the subjects was 25.05 kg/m² andranged from 20.7 to 28.9 kg/m².

All subjects (except one) reported current alcohol use ranging from 1 to20 units per week. No subject was a current smoker. All subjectsreported current caffeine use of 1 to 5 cups or cans per day. No subjecthad been treated with opioids within 1 year prior to screening.

No subject reported any pre-study medication (taken within 2 weeks priorto screening). One subject reported ongoing use of antihistamines forsystemic use by oral tablet or capsule to treat seasonal allergicrhinitis.

Trial medication was administered in the clinic under the supervision ofclinic personnel.

All subjects who were enrolled in the study and who received at leastone dose of trial medication. All randomised subjects who received atleast one treatment, had at least one evaluable plasma profile and hadno major protocol deviations that could have a substantial effect on thebuprenorphine, norbuprenorphine or naloxone plasma concentrationprofile, such as:

-   -   swallowing of study medication (applies to both formulation of        the invention and Suboxone)    -   vomiting within 4 hours after administration of either type of        tablet    -   having a pre-dose quantifiable concentration that is >5% of a        subject's C_(max)

All randomised subjects who received at least one treatment and haddisintegration or acceptability data present for at least one treatment.

Pharmacokinetic (PK) variables were based on plasma concentrations ofbuprenorphine, norbuprenorphine (a metabolite of buprenorphine) andnaloxone and were calculated using standard, non-compartmental methods.The PK non-compartmental analysis was performed using WinNonlin™Professional version 5.2. Data permitting, the following parameters weredetermined:

-   t_(lag) lag time before the start of absorption-   C_(max) maximum plasma concentration-   t_(max) time to reach maximum plasma concentration-   AUC_(0-t) area under the plasma concentration-time curve from time    zero to the time of the last quantifiable plasma concentration-   AUC₀₋₄₈ area under the plasma concentration-time curve from time    zero to 48 hours post-dose-   MR metabolic ratio

In addition, the relative bioavailability (F_(rel)) of formulation ofthe invention to Suboxone was derived based on dose-adjusted PK data.

Subjects were classified as evaluable or non-evaluable with respect tothe PK evaluation by the pharmacokineticist after examining the subjectsPK profiles and taking into account any deviations with respect to thoselisted above. The PK analyses based on the PK population included onlythose subjects with evaluable PK data.

Actual blood sampling times for buprenorphine, norbuprenorphine andnaloxone were converted to a time from dosing (elapsed time). Elapsedtimes were listed by subject for each treatment, together with theindividual buprenorphine, norbuprenorphine and naloxone concentrations.Elapsed times were used in the PK analysis.

The buprenorphine, norbuprenorphine and naloxone concentrations weresummarised by descriptive statistics of number of missing samples,number of samples less than the lower limit of quantification (<LOQ), n,arithmetic mean, SD, CV(%), geometric mean, 95% confidence intervals(CI) for the arithmetic mean, median, minimum and maximum. Allbuprenorphine, norbuprenorphine and naloxone concentrations <LOQ wereset to zero for the purpose of calculating descriptive statistics. If atany time-point ⅓ or more of subjects had values <LOQ, descriptivestatistics were not calculated.

The PK parameters C_(max), AUC_(0-t) and AUC₀₋₄₈ of buprenorphine,norbuprenorphine and naloxone were compared between treatments using amixed effects Analysis of Variance (ANOVA) procedure.

Arithmetic mean (+SEM) analyte concentration-time plasma profiles arepresented in linear scale plots for each analyte in FIGS. 1(buprenorphine), 2 (norbuprenorphine) and 3 (naloxone) with bothtreatments included on each plot. It can be seen from these figuresthat, for both buprenorphine and norbuprenorphine after administrationof formulation of the invention (diamonds), and Suboxone (squares),plasma concentrations of all three analytes increased to a maximum thendeclined in a biphasic manner.

In relation to other PK parameters:

-   -   (i) on average, the lag time was slightly shorter after        treatment with formulation of the invention compared to Suboxone        by 15% for buprenorphine, 29% for norbuprenorphine and 34% for        naloxone;    -   (ii) the range of times at which maximal concentrations were        attained (t_(max)) was similar between treatments for all        analytes. Median t_(max) values were less than or equal to 1 h        for buprenorphine and naloxone indicating rapid sublingual        absorption following administration of both formulation of the        invention and Suboxone. For norbuprenorphine, t_(max) was        generally similar to buprenorphine after both treatments        indicating metabolism of buprenorphine to norbuprenorphine was        rapid;    -   (iii) the mean metabolite ratios exceeded 0.5 indicating        extensive metabolic conversion of buprenorphine to        norbuprenorphine, with conversion being 31% lower following        administration of formulation of the invention compared to        Suboxone. This result is significant as it means that more        buprenorphine is absorbed sublingually in the case of        formulation of the invention;    -   (iv) the doses of both buprenorphine and naloxone were lower in        the formulation of the invention, but mean systemic exposure, in        terms of C_(max) and AUC, of buprenorphine and naloxone were        higher when compared to Suboxone, and, as stated above, the        values were lower for norbuprenorphine; and    -   (v) the mean relative bioavailabilities of formulation of the        invention to Suboxone were 1.659 and 2.056 for buprenorphine and        naloxone respectively, indicating higher dose-normalised        systemic exposure following administration of formulation of the        invention. For norbuprenorphine the dose-normalised systemic        exposure appeared to be similar between treatments with a mean        relative bioavailability of 1.084. The buprenorphine result is        surprising. The reported relative bioavailability of a        sublingually-administered ethanol solution comprising        buprenorphine (where conditions are theoretically optimised for        rapid absorption over the sublingual mucosa) compared to        Suboxone was reported to be 1.5 (see Compton et al, Drug and        Alcohol Dependence, 82, 25 (2006)). The fact that the relative        number reported in this study for a solid sublingual tablet was        even higher than that reported for a solution is remarkable.

Disintegration time of the tablets was assessed by either a nurse or aphysician by mouth inspections, and was also reported by the subjects,who were given thorough instructions of the dosing procedures prior todosing on Day 1 in both treatment periods, including the procedures forobserver and subject assessments of disintegration. Subjects were toreport any premature swallowing.

The sublingual space and the tablet were examined to determine the timeto disintegration. The tablet residues were characterised as ‘intact’,‘fragments’, ‘paste like residue’ or ‘dissolved’. Inspections werecarried out every 2 minutes and the findings recorded until the tabletwas completely disintegrated. In addition, the subject was instructed toindicate when they thought the IMP was dissolved by raising their handor to indicate whether they had swallowed the tablet before it wasdissolved. The time of dissolution or swallowing was recorded.

Median time to non-intact tablets was 2 minutes for the formulation ofthe invention and was 8 minutes for Suboxone.

SUMMARY AND CONCLUSIONS

The above-reported parameter ratios suggest that the formulation of theinvention resulted in slightly higher plasma buprenorphine and naloxoneconcentrations and slightly lower plasma norbuprenorphine concentrationsthan the comparator. The former result is despite the initial dose beinglower which indicates that it may be possible to reduce dose stillfurther. Tablets comprising formulations of the invention alsodisintegrated faster than the comparator.

Example 3

Buprenorphine/Naloxone Sublingual Tablets II

3.97 g of micronized naloxone hydrochloride dihydrate was mixed togetherwith microcrystalline cellulose (20.00 g; Avicel™ PH102 (mean particlesize 100 μm), FMC Biopolymer) and croscarmellose sodium (7.20 g;AcDiSol™, FMC Biopolymer) in a tumble blender (Turbula, WAG,Switzerland) for 40 hours.

14.04 g of micronised buprenorphine hydrochloride was mixed togetherwith mannitol (130.30 g; Pearlitol™ 200SD, Roquette, Lestrem, France),sieved citric acid (6.00 g; fine granular 16/40 grade, DSM, Switzerland,Basel) and sieved (to avoid agglomeration), sodium citrate (19.50 g)Emprove™ cryst., Merck, Darmstadt, Germany) and blended in a tumbleblender for 42 hours.

Menthol (2.00 g; Emprove™ cryst., Merck KGaA, Darmstadt, Germany) wasmortared until a fine powder was formed and was blended with silicondioxide, colloidal (0.20 g; Aerosil™ 200 Pharma), (1:1 volume ratio).

Sucralose (6.00 g, Merck KGaA, Darmstadt, Germany) was added to thebuprenorphine premix. The naloxone premix and the rest of the silicondioxide colloidal (2.80 g) were added by co-sieving into thebuprenorphine premix. The menthol-silicon dioxide blend was added bysieving to the buprenorphine premix and all ingredients were mixed for 1hour.

Sodium stearyl fumarate (8.00 g; Pruv™, JRS Pharma, Polanco, Spain) wasthen added by sieving into this mixture and mixing continued in thetumble blender for 10 minutes.

The final powder mixture was then compressed into tablets in a tabletmachine (Korsch EK0) equipped with 7 mm round, flat faced, radius-edgedpunches, to a tablet weight of 110 mg and a tablet crushing strength of30-35 N.

Example 4

In Vivo Experiment

Placebo tablets prepared according to the procedure described in Example1 above (excluding buprenorpine, but including naloxone) were firstadministered sublingually.

Sublingual saliva pH was measured in vivo using a Schott CG 842P pHMeter attached to a Schott Flatrode™-electrode (pH 0-14, 0-60° C.). TheFlatrode™ has a super-flat membrane for surface measurements and arobust plastic shaft with a ring diaphragm, which guarantees a quickresponse via enhanced contact between the sample and reference. Thediameter of the flat surface of the electrode is 6.0 mm giving ameasuring surface of 0.28 cm².

The Flatrode was positioned (at an open mouth angle of 45°) gentlybehind the lower teeth, just beside the tablet in the mouth. A verygentle pressure was applied in order to measure pH in saliva rather thanvenous blood pH (typically pH 7.4).

pH was measured at time intervals of 0, 30, 60 and 90 seconds (over 5seconds until a stable value was observed). Care was taken to avoidaccidental withdrawal of dissolved powder by the electrode. The mouthwas shut between measurements with no active swallowing.

Triplicate runs were carried out to ensure a reliable pH-profile.Between runs, the mouth was washed thoroughly with water and pH measuredprior to administration to obtain a new zero-value.

The results indicated that the pH decrease peaked at around 35-40seconds. It can be seen from FIG. 4 that the body rapidly compensatesfor the modified pH and also slightly overcompensates, and that thewindow of opportunity (i.e. the time range with a 0.5 pH unit decrease(at least) compared to resting pH) for increased solubility ofbuprenorphine is only about 80 seconds, starting after 10 seconds (n=4).

Example 5

Comparative In Vitro Small-Volume Funnel Dissolution Experiment I

In addition to the sublingual tablets described in Example 3 above, twoother otherwise identical batches of sublingual tablets were preparedusing the same methodology, except that, in one case, the buprenorphinehydrochloride was not micronized, and in the other, no citric acid andsodium citrate were included (instead a further 12.75 mg per tablet ofmannitol was included.

Tablets form the three above-mentioned tablet batches, as well asSuboxone tablets (buprenorphine 8 mg/naloxone 2 mg; Reckitt BenckiserHealthcare Ltd, Hull, UK) were placed on top of a Porosity 1 20 mmdiameter silica filter in a 55 mm (upper inner diameter) glass funnel.

Potassium phosphate buffer with a pH of 6.8 (USP/NF), which mimicssaliva, was allowed to drip through a soft PVC plastic tube with aninner diameter of 3 mm onto the tablets at a rate, set by a peristalticpump (Flocon 1003), of 2 mL per minute. The distance between the end ofthe plastic tube and the silica filter in the funnel was set atapproximately 7.5 cm, in order, along with the dripping rate, tocorrespond to a force similar to the pressure of the underside of thetongue. The small amounts of water involved endeavour to mimic the lowamounts of water available in vivo under the human tongue.

pH was measured over time using a Mettler Toledo InLab Expert Proelectrode (pH 0-14; 0-100° C.) attached to standard Mettler Toledo 340pH meter positioned at the outlet of the glass funnel.

To measure the release of active pharmaceutical ingredients over timefrom the tablets, a glass beaker equipped with a magnetic stirrercontaining 490 mL of potassium phosphate buffer pH 6.8 (USP/NF)collected the drops from the funnel.

800 μL samples were withdrawn from the beaker using a calibratedmicropipette at intervals of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0,4.5, 5.0, 10.0, 15.0 and 20.0 minutes. These samples were emptied into 1mL vials already containing 200 μL of diluted phosphoric acid. Noadditional buffer was added to the collection beaker to compensate. Itstarted with a volume of 490 mL and ended with a volume of 520 mL (thedifference between 40 mL added to the beaker over 20 minutes, and 10.4mL removed in total (13×0.8 mL) is 29.6 mL (i.e. about 30 mL)). It wasdecided to start at 490 mL instead of 485 mL to be as close to 500 mLfor as long a period as possible. The exact individual volumes were ofcourse calculated for each sample.

Three tablets from each of the four tablet table batches in the trialwere analysed as release test samples. Amounts of buprenorphine andnaloxone were measured using HPLC (Agilent 1000; Diode array-detector,gradient pump, autosampler, column oven), with a gradient method with UVdetection at 210 nm.

pH was plotted over time for the following four tablet batches and theresults are shown in FIG. 5 (tablets prepared according to Example 3(squares); non-micronised buprenorphine equivalents (crosses);equivalents without citric acid/sodium citrate (diamonds); and Suboxone(triangles)). The dashed line in FIG. 5 is the superimposed in vivoprofile from FIG. 4.

The drug release profiles over the first 5 minutes for buprenorphine andnaloxone are presented in FIGS. 6, and 7, respectively. AlthoughSuboxone has a 23% higher drug loading than all of the other tablets, itproduces a buprenorphine release after 20 minutes through the funnel ofonly 75% of that of the tablets according to the invention. Thedifference is most noticeable over the first 5 minutes.

Example 6

Buprenorphine/Naloxone Sublingual Tablets III

336.0 g of micronized naloxone hydrochloride dihydrate was mixedtogether with microcrystalline cellulose (2000.0 g; Avicel™ PH102 (meanparticle size 100 μm), FMC Biopolymer, Wallington, Little Island, Co.Cork, Ireland) and croscarmellose sodium (720.0 g; AcDiSol™, FMCBiopolymer, Wallington, Little Island, Co. Cork, Ireland) in a 12 Ldouble cone blender (Sewin, Zickert systems, Kungsbacka, Sweden) for 3hours.

Citric acid (600.0 g; fine granular 16/40 grade, DSM, Switzerland,Basel), sodium citrate (1950.0 g Emprove™ cryst., Merck, Darmstadt,Germany) and silicon dioxide, colloidal (480.0 g Aerosil™ 200 Pharma,Evonik Degussa GmbH, Rheinfelden, Germany) were deagglomerated togetherwith Quadro comil apparatus (Quadro Engineering, Ontario, Canada) andpremixed with two thirds of a pre-measured amount of mannitol (8737.3 g;Pearlitol™ 200SD, Roquette, Lestrem, France) in a 60 L double coneblender (Sewin, Zickert systems, Kungsbacka, Sweden) for 5 minutes.

1188.0 g of the micronised buprenorphine hydrochloride was added to thepremix and the other third of the mannitol (4368.7 g) was added on topof the buprenorphine hydrochloride and all ingredients were mixed for 3hours.

Menthol (200.0 g; Emprove™ cryst., Merck KGaA, Darmstadt, Germany) wasmilled with Quadro comill. Silicon dioxide, colloidal (20.0 g) andmilled menthol (1:1 volume ratio) was processed with Quadro comill inorder to deagglomerate the silicon dioxide (colloidal).

Sucralose (600.0 g, Merck KGaA, Darmstadt, Germany), the naloxone premixand the menthol-silicon dioxide blend were added to the buprenorphinepremix and all ingredients were mixed for 1 hour.

Sodium stearyl fumarate (800.0 g; Pruv™, JRS Pharma, Polanco, Spain) wasdeagglomerated with Quadro comil and added to double cone blender andmixed for 10 minutes.

The final powder mixture was then compressed into tablets in a tabletmachine (Korsch XL100, Korsch AG, Berlin, Germany) equipped with 7 mmround, flat faced, radius-edged punches, to a tablet weight of 110 mgand a tablet crushing strength of 30-35 N.

Example 7

Buprenorphine/Naloxone Sublingual Tablets IV

200,000 100 mg buprenorphine/naloxone (4:1 dose ratio) tabletscomprising a 1.4 mg dose of buprenorphine (calculated as the free base)were prepared using essentially the same procedure as described inExample 6.

Example 8

Buprenorphine/Naloxone Sublingual Tablets V

200,000 110 mg buprenorphine/naloxone (4:1 dose ratio) tabletscomprising a 5.7 mg dose of buprenorphine (calculated as the free base)were prepared using essentially the same procedure as described inExample 6.

Example 9

Comparative In Vitro Small-Volume Funnel Dissolution Experiment II

Using the in vitro small-volume funnel dissolution procedure describedin Example 5, pH profiles (measurement of pH over time) were obtainedfor:

-   -   (a) buprenorphine/naloxone sublingual tablets prepared as        described in Example 8;    -   (b) buprenorphine/naloxone sublingual tablets prepared        essentially as described in Example 8, except that the citric        acid and sodium citrate were included during the mixing step in        which the two APIs are mixed together;    -   (c) buprenorphine/naloxone sublingual tablets prepared        essentially as described in Example 8, but without citric acid        (i.e. sodium citrate only);    -   (d) buprenorphine/naloxone sublingual tablets prepared        essentially as described in Example 8, but without sodium        citrate (i.e. citric acid only);    -   (e) buprenorphine/naloxone sublingual tablets prepared        essentially as described in Example 8, except that tartaric acid        (Sigma-Aldrich) was used instead of citric acid and sodium        citrate; and    -   (f) Suboxone® film (8 mg buprenorphine/2 mg naloxone; Reckitt        Benckiser Healthcare Ltd, Hull, UK).

In the case of tablets (c), and (d), an equivalent amount of mannitolwas employed instead of the citric acid, and the sodium citrate,respectively, that was excluded. In the case of tablets (e), 2 mg (pertablet) of tartaric acid and an extra 10.75 mg (per tablet) of mannitolwere employed.

The results are shown in FIG. 8 (tablets (a)—diamonds; tablets (b)—blacktriangles; tablets (c)—white triangles; tablets (d)—black squares;tablets (e)—white squares; and Suboxone films (f)—circles). Alsosuperimposed on FIG. 8 are:

-   -   (i) the in vivo profile from FIG. 4 (dashed line); and    -   (ii) the in vitro pH profile previously obtained for Suboxone®        tablets (solid line; originally presented in FIG. 5).

The drug release/dissolution profiles over the first 5 minutes forbuprenorphine are presented in FIG. 9. It can be clearly seen from FIGS.8 and 9 taken together that drug dissolution correlates strongly withhow much the pH is lowered during first 1 minute to 2 minutes after thestart of the experiment (corresponding to sublingual administration invivo). It can also be seen that the largest pH drop, and the highestdissolution rate, were obtained when citric acid alone was used.

The invention claimed is:
 1. A pharmaceutical composition in the form ofa tablet suitable for sublingual administration, which comprises:buprenorphine or a pharmaceutically acceptable salt thereof provided inthe form of microparticles, particles comprising citric acid, whichmicroparticles of buprenorphine or salt thereof and particles comprisingcitric acid are in contact with each other, naloxone or apharmaceutically acceptable salt thereof provided in the form ofparticles, and a disintegrant, wherein the dose ratio of buprenorphineto naloxone (calculated as the free bases) is 4:1, and wherein the doseof buprenorphine (calculated as the free base) is 6 mg (±5%) and which,following administration, produces a mean area under the plasmaconcentration-time curve from time zero to the last concentrationextrapolated to infinity based on the elimination rate constant forbuprenorphine that is between 25 ng.h/mL and 40 ng.h/mL.
 2. Thecomposition as claimed in claim 1, wherein the mean area under theplasma concentration-time curve for buprenorphine is between 28 ng.h/mLand 36 ng.h/mL.
 3. The composition as claimed in claim 1, which,following administration, also produces a mean maximum plasmaconcentration for buprenorphine that is between about 3.0 ng/mL andabout 5.6 ng/mL.
 4. The composition as claimed in claim 3, wherein themean maximum plasma concentration for buprenorphine is between about 3.0ng/mL and about 4.5 ng/mL.
 5. The composition as claimed in claim 2,which, following administration, also produces a mean maximum plasmaconcentration for buprenorphine that is between about 3.0 ng/mL andabout 5.6 ng/mL.
 6. The composition as claimed in claim 5, wherein themean maximum plasma concentration for buprenorphine is between about 3.0ng/mL and about 4.5 ng/mL.
 7. The composition as claimed in claim 1,which, following administration, produces a mean maximum plasmaconcentration for naloxone that is between about 150 pg/mL and about 300pg/mL.
 8. The composition as claimed in claim 1, which, followingadministration, produces a mean maximum plasma concentration fornaloxone that is between about 150 pg/mL and about 250 pg/mL.
 9. Thecomposition as claimed in claim 2, which, following administration,produces a mean maximum plasma concentration for naloxone that isbetween about 150 pg/mL and about 300 pg/mL.
 10. The composition asclaimed in claim 2, which, following administration, produces a meanmaximum plasma concentration for naloxone that is between about 150pg/mL and about 250 pg/mL.
 11. The composition as claimed in claim 3,which, following administration, produces a mean maximum plasmaconcentration for naloxone that is between about 150 pg/mL and about 300pg/mL.
 12. The composition as claimed in claim 3, which, followingadministration, produces a mean maximum plasma concentration fornaloxone that is between about 150 pg/mL and about 250 pg/mL.
 13. Thecomposition as claimed in claim 4, which, following administration,produces a mean maximum plasma concentration for naloxone that isbetween about 150 pg/mL and about 300 pg/mL.
 14. The composition asclaimed in claim 4, which, following administration, produces a meanmaximum plasma concentration for naloxone that is between about 150pg/mL and about 250 pg/mL.
 15. The composition as claimed in claim 5,which, following administration, produces a mean maximum plasmaconcentration for naloxone that is between about 150 pg/mL and about 300pg/mL.
 16. The composition as claimed in claim 5, which, followingadministration, produces a mean maximum plasma concentration fornaloxone that is between about 150 pg/mL and about 250 pg/mL.
 17. Thecomposition as claimed in claim 6, which, following administration,produces a mean maximum plasma concentration for naloxone that isbetween about 150 pg/mL and about 300 pg/mL.
 18. The composition asclaimed in claim 6, which, following administration, produces a meanmaximum plasma concentration for naloxone that is between about 150pg/mL and about 250 pg/mL.
 19. The composition as claimed in claim 1,wherein the particles of naloxone or salt thereof are microparticles.